This invention relates to the fields of pharmaceutical and organic chemistry and provides novel benzothiophene compounds which are useful for the inhibition of the various medical conditions associated with postmenopausal syndrome, as well as estrogen-dependent diseases including cancer of the breast, uterus, and cervix.
xe2x80x9cPostmenopausal syndromexe2x80x9d is a term used to describe various pathological conditions which frequently affect women who have entered into or completed the physiological metamorphosis known as menopause. Although numerous pathologies are contemplated by the use of this term, three major medical conditions of postmenopausal syndrome are the source of the greatest long-term medical concern: osteoporosis, cardiovascular effects such as hyperlipidemia, and estrogen-dependent cancer such as breast and uterine cancer.
Osteoporosis, which generally includes a group of disorders which arise from diverse etiologies, is characterized by the net loss of bone mass per unit volume. The consequence of this loss of bone mass and resulting bone fracture is the failure of the skeleton to provide adequate structural support for the body. One of the most common types of osteoporosis is that associated with menopause. Most women lose from about 20% to about 60% of the bone mass in the trabecular compartment of the bone within three to six years after the cessation of menses. This rapid loss is generally associated with an increase of bone resorption and formation. However, the resorptive cycle is more dominant and the result is a net loss of bone mass.
Osteoporosis is a common and serious disease among postmenopausal women. There are an estimated 25 million women in the United States who are afflicted with this disease. The results of osteoporosis disease""s sequelae are personally harmful and often result in the need for extensive and long term medical support (hospitalization and nursing home care). This is especially true in elderly patients. Additionally, although osteoporosis is not generally thought of as a life threatening condition, a 20% to 30% mortality rate is related with hip fractures in elderly women. A large percentage of this mortality rate can be directly associated with postmenopausal osteoporosis.
The trabecular tissue is the most vulnerable bone tissue to the effects of postmenopausal osteoporosis. This tissue is often referred to as spongy or cancellous bone and is particularly concentrated near the ends of the bone (near the joints) and in the vertebrae of the spine. The trabecular tissue is characterized by small osteoid structures which inter-connect with each other, as well as the more solid and dense cortical tissue which makes up the outer surface and central shaft of the bone. This interconnected network of trabeculae gives lateral support to the outer cortical structure and is critical to the biomechanical strength of the overall structure. In postmenopausal osteoporosis, it is loss of the trabeculae which leads to the failure and fracture of bone. In light of the loss of the trabeculae in postmenopausal women, it is not surprising that the most common fractures are those associated with bones which are highly dependent on trabecular support, e.g., the vertebrae and the neck of the weight bearing bones, such as the femur and the fore-arm. Indeed, hip fracture, collies fractures, and vertebral crush fractures are hallmarks of postmenopausal osteoporosis.
At this time, the generally accepted method for treatment of postmenopausal osteoporosis is estrogen replacement therapy (ERT). Although ERT is generally successful, patient compliance with this therapy is low primarily because estrogen treatment frequently produces undesirable side effects.
Prior to menopause, most women have less incidence of cardiovascular disease than age-matched men. Following menopause, however, the rate of cardiovascular disease in women, such as hyperlipidemia, increases to match the rate seen in men. This rapid increase in the incidence of cardiovascular disease has been linked, in part, to the loss of estrogen and to the loss of estrogen""s ability to regulate serum lipids. The nature of estrogen""s ability to regulate serum lipids is not well understood, but evidence to date indicates that estrogen can upregulate the low density lipid (LDL) receptors in the liver to remove excess cholesterol. Additionally, estrogen appears to have some effect on the biosynthesis of cholesterol, as well as other beneficial effects on cardiovascular health.
It has been reported in the literature that postmenopausal women undergoing estrogen replacement therapy have a return of serum lipid levels to concentrations similar to those of the premenopausal state. Thus, estrogen would appear to be a reasonable treatment for this condition. However, the side-effects of ERT are not acceptable to many women, thus limiting the use of this therapy. An ideal therapy for this condition would be an agent which would regulate the serum lipid levels like estrogen, but would be devoid of the side-effects and risks associated with estrogen therapy.
The third major pathology associated with postmenopausal syndrome is estrogen-dependent cancer, primarily breast and uterine cancer. Although such neoplasms are not solely limited to postmenopausal women, they are more prevalent in the older postmenopausal population. Current chemotherapy of these cancers has relied heavily on the use of estrogen agonist/antagonist compounds, such as tamoxifen. Although such mixed agonist/antagonists have beneficial effects in the treatment of these cancers, the estrogenic side-effects are tolerable in only acute life-threatening situations. These agents have stimulatory effects on certain cancer cell populations in the uterus due to their estrogenic (agonist) properties and therefore, arecontraproductive in some cases. A better therapy for the treatment of these cancers would be an agent which is an antiestrogenic compound in cancerous tissue, having negligible or no estrogen agonist properties on other reproductive tissues.
In response to the clear need for new pharmaceutical agents which are capable of alleviating the symptoms of, inter alia, postmenopausal syndrome, the present invention provides new compounds, pharmaceutical compositions thereof, and methods of using such compounds for the inhibition of postmenopausal syndrome and other estrogen-related pathological conditions such as those mentioned herein.
The present invention relates to compounds of formula 
wherein:
R is independently at each occurrence NHC(O)R1, OR1, or SR1;
R1 is C1-C6 alkyl or aryl;
R2 is pyrrolidin-1-yl, pipiperidin-1-yl, or hexamethyleneimin-1-yl; and
X is Cxe2x95x90O, CHxe2x80x94OH, CH2, O, or S; or a pharmaceutically acceptable salt or solvate thereof.
The present invention further relates to pharmaceutical formulations containing compounds of formula I and the use of such compounds for alleviating the symptoms of postmenopausal syndrome, particularly osteoporosis, cardiovascular-related pathological conditions, and estrogen-dependent cancer.
As used herein, the term xe2x80x9cC1-C4 alkylxe2x80x9d represents a methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, cyclobutyl, s-butyl, or a t-butyl group. The term xe2x80x9cC1-C6 alkylxe2x80x9d includes xe2x80x9cC1-C4 alkylxe2x80x9d groups in addition to straight, branched or cyclic alkyl groups having five or six carbon atoms and also includes, but is not limited to, pentyl, isopentyl, hexyl, 2-methylpentyl, cyclopentyl, cyclohexyl, and like groups.
The term xe2x80x9carylxe2x80x9d represents phenyl, benzyl, substituted phenyl, and substituted benzyl groups.
The terms xe2x80x9csubstituted phenylxe2x80x9d and xe2x80x9csubstituted benzylxe2x80x9d represent a phenyl and benzyl group substituted with one to five moieties chosen from the group consisting of halo, hydroxy, nitro, C1-C4 alkyl, C1-C4 alkoxy, trichloromethyl, and trifluoromethyl. Examples of a substituted phenyl group include 4-chlorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3,4-dibromophenyl, 3-chloro-4-fluorophenyl, 2-fluorophenyl, 4-hydroxyphenyl, 3-hydroxyphenyl, 2,4-dihydroxyphenyl, 3-nitrophenyl, 4-nitrophenyl, 2,4-dinitrophenyl, 4-methylphenyl, 4-ethylphenyl, 4-methoxyphenyl, 4-propylphenyl, 4-n-butylphenyl, 4-t-butylphenyl, 3-fluoro-2-methylphenyl, 2,3-difluorophenyl, 2,6,difluorophenyl, 2,6-dimethylphenyl, 2-fluoro-5-methylphenyl, 2,4,6-trifluorophenyl, 2-trifluoromethylphenyl, 2-chloro-5-trifluoromethylphenyl, 3,5-bis-(trifluoromethyl)phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 3,5-dimethoxyphenyl, 2-methyl-4-nitrophenyl, 4-methoxy-2-nitrophenyl, and the like. Examples of a substituted benzyl group would include all the compounds named when the word xe2x80x9cbenzylxe2x80x9d is substituted for the word xe2x80x9cphenylxe2x80x9d in all the previously mentioned examples of a substituted phenyl group.
The term xe2x80x9chydroxy protecting groupxe2x80x9d denotes a group understood by one skilled in the organic chemical arts of the type described in Chapter 2 of xe2x80x9cProtective Groups in Organic Synthesis, 2nd Edition, T. H. Greene, et al., John Wiley and Sons, New York, 1991, hereafter xe2x80x9cGreenexe2x80x9d. 
The term xe2x80x9cphase transfer catalystxe2x80x9d refers to a salt in which the cation has large nonpolar substituent groups which confer good solubility on the salt in organic solvents. The most common examples are tetraalkylammonium and tetraalkylphosphonium ions e.g. tetraalkylammonium chloride or bromide or (C8-C10 trialkyl)methylammonium chloride (Adogen(copyright) 464).
Although the free-base form of formula I compounds can be used in the methods of the present invention, it is preferred to prepare and use a pharmaceutical salt form. Typical pharmaceutical salts include those salts prepared by reaction of the compounds of the present invention with a mineral or organic acid. Such salts are known as acid addition salts. Thus, the term xe2x80x9cpharmaceutical saltxe2x80x9d refers to acid addition salts of a compound of formula I which are substantially non-toxic at the doses administered and are commonly known in the pharmaceutical literature. See e.g. Berge, S. M, Bighley, L. D., and Monkhouse, D. C., J. Pharm. Sci., 66, 1, 1977.
Examples of such pharmaceutically acceptable salts are the iodide, acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, g-hydroxybutyrate, b-hydroxybutyrate, butyne-1,4-dioate, hexyne-1,4-dioate, hexyne-1,6-dioate, caproate, caprylate, chloride, cinnamate, citrate, decanoate, formate, fumarate, glycollate, heptanoate, hippurate, lactate, malate, maleate, hydroxymaleate, malonate, mandelate, mesylate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, terephthalate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, propiolate, propionate, phenylpropionate, salicylate, sebacate, succinate, suberate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfite, sulfonate, benzenesulfonate, p-bromophenylsulfonate, chlorobenzenesulfonate, propanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, p-toluenesulfonate, xylenesulfonate, tartarate, and the like of a compound of formula I.
By xe2x80x9cpharmaceutical formulationxe2x80x9d it is meant that in a formulation containing the compound of formula I, the carrier, diluent, excipients, and salt must be compatible with the other ingredients of the formulation, and not deleterious to the recipient thereof.
The term xe2x80x9csolvatexe2x80x9d represents an aggregate that comprises one or more molecules of the solute, such as a formula I compound, with one or more molecules of solvent.
As used herein, the term xe2x80x9ceffective amountxe2x80x9d means an amount of compound of the present invention which is capable of inhibiting the symptoms of the various pathological conditions herein described.
The terms xe2x80x9cinhibitxe2x80x9d or xe2x80x9cinhibitingxe2x80x9d bear their usual meaning which includes prohibiting, treating, alleviating, ameliorating, halting, restraining, slowing or reversing the progression, or reducing the severity of a pathological symptom related to or resultant from post menopausal syndrome. As such, these methods include both medical therapeutic (acute) and/or prophylactic (prevention) administration as appropriate.
While all of the compounds of the present invention are useful, certain of the compounds are particularly interesting and are preferred. The following listing sets out several groups of preferred compounds. It will be understood that each of the listings may be combined with other listings to create additional groups of preferred compounds.
aa) X is Cxe2x95x90O;
ab) X is O;
ac) R at each occurrence is SR1;
ad) R at each occurrence is S-(C1-C4 alkyl);
ae) R at each occurrence is S-phenyl;
af) R at each occurrence is OR1;
ag) R at each occurrence is O-(C1-C4 alkyl);
ah) R at each occurrence is NHC(O)-R1;
ai) R at each occurrence is NHC(O)-phenyl;
aj) R2 is piperidin-1-yl;
ak) the compound of formula I is a salt; and
al) the compound of formula I is the hydrochloride salt.
Specific preparations of compounds of the present invention are described herein, in Examples 1-5. Modification to the methods described below may be necessary to accommodate reactive functionalities of particular substituents. Such modification would be both apparent to, and readily ascertained by, those skilled in the art. The following schemes generally illustrate the preparation of compounds of formula I.
The compounds of formula I where R at each occurrence is the same may be prepared from compounds of formula II as illustrated in Scheme 1 below where Xxe2x80x2 is Cxe2x95x90O, O, or S, Y is halo or hydroxy, and R and R2 are as described supra. 
When Y is halo, compounds of formula I(a) may be prepared by dissolving or suspending a compound of formula II in a suitable organic solvent, in the presence of a suitable base, and adding a compound of formula III. The presence of a phase transfer catalyst is also an optional reagent depending on the solvent system and base as discussed below. Additionally, when Y is chloro, sodium iodide may also be employed to aid in the displacement reaction. Once all the ingredients are combined, the reaction is allowed to proceed at temperatures ranging from 0xc2x0 C. to the reflux temperature of the reaction mixture. Typically the reaction is performed at ambient temperatures. The reaction time will depend upon the compound of formula III. When R is OR1 or NHC(O)R1l, reaction times generally will range from about 20 minutes to 2 hours. When R is SR1 however, reaction times tend to be longer and range from about 8 to 24 hours. A reaction time of about 18 hours is typical.
Suitable organic solvents include, but are not limited to, N,N-dimethylpropyleneurea (DMPU), methylene chloride, tetrahydrofuran, chloroform, ethyl acetate, acetonitrile, mixtures thereof, and the like. DMPU and methylene chloride individually are typically preferred solvents. Suitable bases include but are not limited to metal hydrides and metal hydroxides, e.g. sodium, potassium, or lithium hydride and hydroxide. Sodium hydride and aqueous sodium hydroxide individually are typically preferred bases. When aqueous sodium hydroxide is employed the reaction is preferably run in the presence of a phase transfer catalyst. Adogen(copyright) 464 is a preferred phase transfer catalyst.
The compound of formula III is typically employed in a stoichiometric excess. For example, when R is SR1, from 2 to about 2.5 equivalents, relative to the compound of formula II, is generally employed, while 2.3 equivalents is typically preferred. When R is OR1 or NHC(O)R1, from 9.5 to 10.5 equivalents are preferably employed while 10.0 equivalents are typically preferred. The base is also generally employed in a molar excess. For example, from 3.5 to about 6.5 equivalents are typically employed. When aqueous sodium hydroxide is employed, a preferred amount is about 5.8 to about 6.2 equivalents. When sodium hydride is employed, a preferred amount is about 3.8 to about 4.2 equivalents. The phase transfer catalyst, when used, is employed in a stoichiometric deficiency. Typically, about 0.05 to 0.15 equivalents, relative to the compound of formula II is employed. A preferred amount is about 0.10 equivalents.
Compounds of formula I(a) may also be prepared by the Mitsunobo reaction of a compound of formula II with a compound of formula III where Y is hydroxy. This transformation is accomplished by dissolving or suspending a compound of formula II in a suitable solvent and adding a suitable base, a compound of formula III where Y is hydroxy, triphenyl phosphine, and diethylazodicarboxylate. The resulting mixture is allowed to stir for from 2 to 24 hours at ambient temperature, but the reaction is typically complete in from 16 to 20 hours. The reaction is preferably allowed to run for about 18 hours. Suitable solvents include anhydrous solvents, such as methylene chloride, acetonitrile, chloroform, ethyl acetate, mixtures thereof, and the like. Typically, anhydrous tetrahydrofuran is a convenient and preferred solvent. Suitable bases include, but are not limited to, carbonates, bicarbonates, and hydroxides (e.g. lithium, sodium, or potassium carbonate, bicarbonate, or hydroxide), tri-(C1-C4 alkyl)amines (e.g. triethylamine), or aromatic nitrogen containing heterocycles (e.g. pyridine). Triethylamine is a preferred base.
The base is preferably employed in a stoichiometric amount relative to the compound of formula II, but excesses on the order of 0.01 to 0.1 equivalents are acceptable. The compound of formula III, triphenyl phosphine, and diethylazodicarboxylate are typically employed in a molar excess relative to the compound of formula II. The compound of formula III is typically employed in about a 2 to 3 molar excess, while a 2.5 molar excess is a preferred amount. The triphenyl phosphine and diethylazodicarboxylate are usually employed in about a 3.5 to about a 4.5 molar excess while a 4.0 molar excess is typically preferred. For further instruction on conditions and reagents useful in the Mitsunobo reaction see Mitsunobo""s review article in Synthesis, 1, (1981).
The compounds of formula I where R at each occurrence is not the same may be prepared from compounds of formula IV or V as illustrated in Scheme 2 below where Pg is a hydroxy protecting group, R3 has the same scope as R but R and R3 are different within the same molecule, and R, R2, Xxe2x80x2, and Y are as described supra. 
The coupling of a compound of formula III to a compound of formula IV or V may be performed as described above in Scheme 1. Similarly, a compound of formula X may also be coupled to a compound of formula VIII or IX as described above in Scheme 1.
The hydroxy protecting groups in compounds of formula VI and VII may be removed by well known methods in the art. Numerous reactions for the formation and removal of hydroxy protecting groups are described in a number of standard works including, for example, The Peptides, Vol. I, Schrooder and Lubke, Academic Press (London and New York, 1965), (hereafter referred to as The Peptides) and Greene. 
The compounds of formula I where X is CHxe2x80x94OH or CH2 may be prepared from compounds of formula I where X is Cxe2x95x90O essentially as described in U.S. Pat. No. 5,484,798, the teachings of which are hereby incorporated by reference.
The pharmaceutical acid addition salts are typically formed by reacting a compound of formula I in its free base form with an equimolar or excess amount of acid. The reactants are generally combined in a polar organic solvent such as methanol or ethyl acetate. The salt normally precipitates out of solution within about one hour to 10 days and can be isolated by filtration, or the solvent can be stripped off by conventional means.
The pharmaceutical salts generally have enhanced solubility characteristics compared to the compound from which they are derived, and thus are often more amenable to use in pharmaceutical formulations.
Compounds of formula II are well known in the art and may be prepared as described in U.S. Pat. No. 4,358,593 the teachings of which are hereby incorporated by reference. Compounds of formula III and X are also well known in the art and are generally commercially available. Compounds of formula III and X where R or R3 is NHC(O)R1 and Y is hydroxy may also be prepared as described in J.Org.Chem., 57, 1702, (1992).
The compounds of formula IV and V may be prepared from bis-hydroxy protected compounds of formula XI: 
where Pg and Pgxe2x80x2 are different hydroxy protecting groups, by selectively removing one of the hydroxy protecting groups leaving the other intact. Choices of hydroxy protecting groups which facilitate a selective removal and methods for the selective removal of one hydroxy protecting group over the other are well known in the art given the guidance of Greene and The Peptides. One example where selective removal is possible is where one protecting group is benzyl and the other is a C1-C4 alkyl group. The benzyl group may be removed selectively by catalytic hydrogenation. In general, preferred protecting groups are benzyl and C1-C4 alkyl groups and especially preferred are methyl and isopropyl groups.
Methods of preparing differentially protected compounds of formula XI are known in the art. One method, where X is Cxe2x95x90O, may be found in U.S. Pat. No. 5,420,349, the teachings of which are hereby incorporated by reference. Compounds of formula XI where X is O may be prepared as taught in U.S. Pat. No. 5,723,474 the teachings of which are hereby incorporated by reference. Compounds of formula XI where X is S may be prepared essentially as described for compounds of formula XI where X is O.
The optimal time for performing the reactions of Schemes 1-2 can be determined by monitoring the progress of the reaction via conventional chromatographic techniques. Furthermore, it is preferred to conduct the reactions of the invention under an inert atmosphere, such as, for example, argon, or, particularly, nitrogen. Choice of solvent is generally not critical so long as the solvent employed is inert to the ongoing reaction and sufficiently solubilizes the reactants to effect the desired reaction. Intermediate and final products may be purified, if desired by common techniques such as recrystallization or chromatography over solid supports such as silica gel or alumina.
The synthetic steps of the routes described herein may be combined in other ways to prepare the formula I compounds. The discussion of the synthesis is not intended to be limiting to the scope of the present invention, and should not be so construed. Application of the above chemistry enables the synthesis of the compounds of formula I, which would include, but not be limited to:
1) [6-ethylthiomethoxy-2-(4-[ethylthiomethoxy]phenyl)benzo[b]thiophen-3-yl][4-([2-piperidin-1-yl]ethoxy)phenyl]methanol;
2) [6-phenoxymethoxy-2-(4-phenxoxymethoxyphenyl)benzo[b]thiophen-3-yl][4-([2-pyrrolidin-1-yl]ethoxy)phenyl]sulfide;
3) [6-butoxymethoxy-2-(4-butoxyphenoxyphenyl)benzo[b]thiophen-3-yl][4-([2-hexamethyleneimin-1-yl]ethoxy)phenyl]ether;
4) [6-isopropylthiomethoxy-2-(4-[isopropylthiomethoxy]phenyl)benzo[b]thiophen-3-yl][4-([2-piperidin-1-yl]ethbxy)phenyl]methane;
5) [6-Acetamidylmethoxy-2-(4-Acetamidylmethoxyphenyl)benzo[b]thiophen-3-yl][4-([2-pyrrolidin-1-yl]ethoxy)phenyl]methanol; and
6) [6-Propionamidylmethoxy-2-(4-Propionamidylmethoxyphenyl)benzo[b]thiophen-3-yl][4-([2-hexamethyleneimin-1-yl]ethoxy)phenyl]sulfide.
The following Preparations and Examples further illustrate the synthesis of the compounds of the present invention. The examples are not intended to be limiting to the scope of the invention in any respect, and should not be so construed. All experiments were run under positive pressure of dry nitrogen. The terms and abbreviations used in the instant preparations and examples have their normal meanings unless otherwise designated. For example xe2x80x9cxc2x0 C.xe2x80x9d, xe2x80x9cNxe2x80x9d, xe2x80x9cmmolxe2x80x9d, xe2x80x9cgxe2x80x9d, xe2x80x9cLxe2x80x9d, xe2x80x9cMxe2x80x9d, xe2x80x9cHPLCxe2x80x9d, xe2x80x9cEAxe2x80x9d, xe2x80x9cIRxe2x80x9d, and xe2x80x9c1H-NMRxe2x80x9d, refer to degrees Celsius, normal or normality, millimole or millimoles, gram or grams, milliliter or milliliters, molar or molarity, high performance liquid chromatography, elemental analysis, infrared, and proton nuclear magnetic resonance respectively.
Benzamide (25 g, 206 mmol), formaldehyde (37% aqueous, 70 mL, 890 mmol), and potassium carbonate (700 mg, 5 mmol) were mixed in 36 mL of water. The mixture was heated at 45xc2x0 C. long enough to dissolve the reagents and then cooled to room temperature. The reaction was allowed to proceed for 48 hours when 1H NMR indicated that the reaction was complete. The reaction was diluted with about 500 mL of water and crystals began to form and were allowed to continue to form for 18 hours. The crystals were collected by vacuum filtration, washed with water, and vacuum dried at 40xc2x0 C. The filtrate was extracted with ethyl acetate and the organic layer was dried over sodium sulfate, filtered, and evaporated to give a white solid which was also vacuum dried at 40xc2x0C. The lots were combined for a total of 29.0 g of title compound. 93%. 1H NMR consistent with title compound.